E. Bradshaw Bunney, MD

FERNE/EMRA Session: FERNE/EMRA Session:

Treating Ischemic Stroke Treating Ischemic Stroke Patients Using a Patients Using a

3 to 4.5 Hour tPA Window3 to 4.5 Hour tPA Window

E. Bradshaw Bunney, MD

2009 ACEP Scientific Assembly & EMRA Semi-Annual Meetings

Boston, MABoston, MA

October 6, 2009October 6, 2009

E. Bradshaw Bunney, MD

E. Bradshaw BunneyE. Bradshaw Bunney, MD Assoc. Professor

Department of Emergency MedicineUniversity of Illinois at Chicago

Chicago, Illinois

E. Bradshaw Bunney, MD

Attending PhysicianEmergency Medicine

University of Illinois HospitalSwedish American Belvidere Hospital

Chicago, IL

E. Bradshaw Bunney, MD

DisclosuresDisclosures• FERNE Board Member

• FERNE grants by industry

• Participation on industry-sponsored advisory boards and as lecturer in programs supported by industry

E. Bradshaw Bunney, MD

ObjectivesObjectives

• What does the ECASS 3 study tell us?

• How does the ECASS 3 data compare to other studies?

• What other data is available regarding treatment in the 3 - 4.5 hour window?

E. Bradshaw Bunney, MD

Time to Treatment and tPA BenefitTime to Treatment and tPA BenefitmRS 0-1 at day 90

Adjusted odds ratio with 95 % confidence interval by stroke onset to treatment time (OTT)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

Ad

j us t

e d o

dd

s ra

tio

Stroke onset to treatment time (OTT) [min]

60 90 120 150 180 210 240 270 300 330 360

< 3 h 3-4 h > 4 h

Lancet 2004, 363, 368-374

E. Bradshaw Bunney, MD

ECASS 3ECASS 3

• Prospective, randomized, placebo controlled, study

• Is tPA efficacious in the treatment of ischemic stroke in the 3 – 4.5 hour window?

• Primary outcome = mRS 0 - 1 at 90 days• Study mandated by the European

Medicines Agency (EMEA), pharmaceutical approval agency

Hacke, NEJM 2008;359:1317-29

E. Bradshaw Bunney, MD

ECASS 3 CriteriaECASS 3 Criteria

• Inclusion– 18 – 80 years old– Symptoms > 30 min.

• Exclusion– NIHSS > 25– Prior stroke and Diabetes– Oral anticoagulation use– Seizure at onset of symptoms– BP > 185/110 not easily controlled, no IV

drips

Hacke, NEJM 2008;359:1317-29

E. Bradshaw Bunney, MD

ECASS 3 DataECASS 3 Data

• N = 821

• 43 tPA and 48 placebo excluded– Did not treat, age, CT criteria

• Median time to treat = 3:59

Hacke, NEJM 2008;359:1317-29

E. Bradshaw Bunney, MD

ECASS 3 DataECASS 3 Data

• Differences between tPA and placebo groups– NIHSS 10.7 v. 11.6 p=0.003

– History of stroke 7.7 v. 14.1 p=0.03

Hacke, NEJM 2008;359:1317-29

E. Bradshaw Bunney, MD

ECASS 3 DataECASS 3 Data

• Primary out come mRS 0-1

• tPA 219/418 (52.4%)

• Placebo 182/403 (45.2%)

• P = 0.04– OR 1.34 (CI 1.02 – 1.76)

– Absolute improvement 7.2%

Hacke, NEJM 2008;359:1317-29

E. Bradshaw Bunney, MD

ECASS 3 DataECASS 3 Data

• Secondary outcomes– mRS

– Barthel Index

– NIHSS

– Glasgow Outcome Scale

• Global odds ratio 1.28

Hacke, NEJM 2008;359:1317-29

E. Bradshaw Bunney, MD

Types of ICHTypes of ICH

• HI 1 = small petechiae along margin of infarct

• HI 2 = more confluent petechiae without mass effect

• PH 1 = parenchymal ICH• PH 2 = clot exceeding 30% of

infarct area with mass effect

E. Bradshaw Bunney, MD

Symptomatic ICH DefinitionsSymptomatic ICH Definitions• ECASS 3: Any hemorrhage with

neurological deterioration, increase of 4 or more NIHSS, predominant cause of deterioration.

• ECASS 2: Same as ECASS 3 without causal requirement

• NINDS: Suspicion of hemorrhage or neuro deterioration, and finding hemorrhage not previously there on a subsequent CT.

E. Bradshaw Bunney, MD

NINDS sICH Definition NINDS sICH Definition

Hacke, NEJM 2008;359:1317-29

tPA Placebo

NINDS 6.4% 0.6%

ECASS 3 7.9% 3.5%

E. Bradshaw Bunney, MD

ECASS3 sICH Definition ECASS3 sICH Definition

Hacke, NEJM 2008;359:1317-29

tPA Placebo

NINDS N/A N/A

ECASS 3 2.4% 0.2%

E. Bradshaw Bunney, MD

ECASS 3 ConclusionsECASS 3 Conclusions

• tPA significantly improved clinical outcomes in patients with acute ischemic stroke presenting between 3 – 4.5 hours.

• tPA is associated with increased sICH compared to placebo.

Hacke, NEJM 2008;359:1317-29

E. Bradshaw Bunney, MD

ECASS 3 CriticismsECASS 3 Criticisms

• Fewer diabetics compared to NINDS– tPA 14.8% v. 22%, placebo 16.6% v.

20%

• Much lower mean NIHSS– tPA 10.7 v. 14, placebo 11.6 v. 14

• No history of prior stroke and diabetes allowed

Lyden, NEJM 2008;395:1393-95

E. Bradshaw Bunney, MD

Meta-analysisMeta-analysis

• ECASS 1, ECASS 2, ECASS 3, ATLANTIS

• Patients in 3 – 4.5 hour window• Mean age 65• Mean NIHSS 2 – 3 points less in

ECASS 3• Mean onset to drug 4 hours• Diabetes similar among ECASS’s

16%, ATLANTIS 21%

Lansberg, Stroke 2009;40:2438-41

E. Bradshaw Bunney, MD

Meta-analysisMeta-analysis

• mRS 0 – 1, OR 1.31• Global outcome

– mRS– NIHSS– Barthel Index– OR 1.31

• Mortality same, OR 1.04

Lansberg, Stroke 2009;40:2438-41

E. Bradshaw Bunney, MD

SITS-ISTR 3 – 4.5 hourSITS-ISTR 3 – 4.5 hour

• European data base

• Observational study

• Not randomized controlled trial

• Compare 664 treated 3 – 4.5 h with 11865 treated within 3 h.

Wahlgren, Lancet 2008;372:1303-09

E. Bradshaw Bunney, MD

SITS-ISTR 3 – 4.5 hourSITS-ISTR 3 – 4.5 hour

• Median 55 min. later 195 min. v. 140 min.– 60% before 200 min.

• 3 years younger 65 v. 68

• NIHSS lower 11 v. 12

Wahlgren, Lancet 2008;372:1303-09

E. Bradshaw Bunney, MD

SITS-ISTR 3 – 4.5 hourSITS-ISTR 3 – 4.5 hour

• Independence 58% 3-4.5 v. 56%

• sICH 2.2% v. 1.6%

• Mortality 12.7% v. 12.2%

Wahlgren, Lancet 2008;372:1303-09

E. Bradshaw Bunney, MD

Number Needed to TreatNumber Needed to Treat

• Benefit: To improve by 1 or more mRS– 0 – 3 hours 32.3/100 treated– 3 - 4.5 hours 16.4/100 treated

• Harm: To worsen by 1 or more mRS– 0 – 3 hours 3.3/100 treated– 3 – 4.5 hours 2.7/100 treated

Saver, Stroke 2009;40:2433-37

E. Bradshaw Bunney, MD

Number Needed to TreatNumber Needed to Treat

• NNT to benefit by 1 or more mRS is 6

• NNT to harm by 1 or more mRS is 37

• From ECASS 3 NNT to benefit to mRS of 0 – 1 (best outcome) is 14

Saver, Stroke 2009;40:2433-37

E. Bradshaw Bunney, MD

Who should be treated in 3 – 4.5 h?Who should be treated in 3 – 4.5 h?

• Relatively young, 65 +/- 10years old

• Less severe strokes, NIHSS < 11 +/- 6, median in tPA group of ECASS 3 was 9

• Diabetes??

• No one with diabetes and prior stroke

E. Bradshaw Bunney, MD

ConclusionsConclusions

• Meta-analysis and observational studies appear to support the use of tPA beyond the 3 hour window

• Extension of the treatment window to 4.5 hours is being endorsed by many

• Institutions must modify their protocols to adjust for the population treated in the ECASS 3 trial in the 3 – 4.5 hour window

E. Bradshaw Bunney, MD

Questions?Questions?

www.FERNE.org

bbunney@uic.edu